Role Of Itk In Th17 Mediated Inflammation Model Hypersensitivity Pneumonitis

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Hypersensitivity Pneumonitis (HP) is a lung disease caused by repeated inhalation of environmental antigens leading to inflammation, tissue scarring, and some loss of lung function. This pathology is believed to be due to the increased IL-17A, a cytokine secreted predominantly by a subset of T cells, Th17 cells, that induces recruitment of inflammatory cells such as neutrophils and leads to pathology in this disease. The thermophile Sacharopolyspora rectivigula (SR) causes HP in humans, and we have used a murine model of HP, exposure to SR, to study the molecular mechanism of disease development. Using novel IL-17A-GFP reporter mice, our preliminary data suggests that the high levels of IL-17A induced in response to SR are produced in part by CD4+ T cells and not by neutrophils. The Tec family tyrosine kinase Itk is a pharmaceutical target and regulates T cell activation and cytokine production, including Th2 cytokines and IL-17A in conventional Th17 cells. Mice lacking Itk are therefore resistant to developing Th2 cytokine driven allergic lung inflammation. However our experiments indicate that mice lacking Itk develop HP. Histology from these mice indicates an increase in inflammatory cells in lung airways as well as deterioration of lung tissue architecture. Mice lacking Itk also have significant levels of IL-17A mRNA expression in the lung, and an increase in the number of CD4+ IL-17A producing cells. Furthermore, the lack of Itk signaling led to the absence of IL-17A producing [gamma][delta] T cells in the early stage of HP, which recover over the later stage of disease. This phenomenon directly coincides with the emergence of IL-17A producing CD4+[gamma][delta] T cells in the lungs of Itk-/- mice exposed to SR. We conclude that Itk regulated signals are not critical for the production of IL-17A in response to SR, and Itk may therefore differentially regulate the production of IL-17A in different types of T cells. We also show that the inhibition of Itk kinase signaling can be inhibited by targeting allele sensitive Itkas. The block in kinase activity leads to decrease response of response in the BAL and lungs. We investigate the relationship between Th17 cell and T regulatory T cells in an IL-17A driven disease as it relates to Itk signaling. We find that Itk signaling is not altering the proportion or numbers of T regulatory cells. Additionally, we show that iNKT cells are a possible source of IL-17A and this primarily independent of Itk signal as well. Lastly, we investigate the role of IL4Ra signaling and indirectly innate memory phenotype (IMP) cells in HP. Our data shows IL-4 signaling as well as IMP cells play a protective role in the BAL during HP. Furthermore, IL-4Ra and IMP cells are partially responsible for the number of CD4+ T cells seen in HP, which is independent of Itk-/- mice ability to make IL-17A cytokine in SR induced HP. SR induced HP. ! Together, you data show Itk mediate differential immune responses in

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Itk; Hypersensitivity Pneumonitis; T cells


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Bynoe,Margaret S.
Rudd,Brian D

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Ph. D., Immunology

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Doctor of Philosophy

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dissertation or thesis

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